Onychomycosis is a fungal disease of the human nail. The symptoms of this disease are a split, thickened, hardened, and rough nail plates. This is caused by any of a number of organisms and is particularly prevalent in the elderly. Typically fungal infections are treated by topical application of antifungal agents and/or oral administration of antifunal agents. Unlike other fungal infections, there is no topical treatment for onchomycosis which is approved by the United States Food and Drug Administration. It is desirable to treat this disease topically due to the potential for side effects which have been associated with some of the oral treatment regimens. One reason for the absence of a topical treatment is that in this disease, the symptomatic thickened nail plate prevents topical agents from reaching the site of the infection. The target sites for the treatment of onychomycosis reside in the nail plate, nail bed and nail matrix, as set forth in FIG. 1. It has been shown that if the nail barrier is modified, reduced, or eliminated, topical antifungal drug treatment is effective for onychomycosis. For example, both miconazole and ketoconazole have been demonstrated to be effective in topically treating onychomycosis after nail removal. Nevertheless, most consumers would certainly prefer a less dramatic treatment of nail fungal infection than removal of the nail.
The nail plate is thick, hard, dense, and represents a formidable barrier for drugs to be able to penetrate in a therapeutically required quantity. Although nail material is similar to the stratum corneum of the skin, being derived from epidermis, it is composed primarily of hard keratin, which is highly disulfide-linked, and is approximately 100-fold thicker than stratum corneum. In order to deliver a sufficient amount of drug into the nail plate, the permeability of the nail plate to the drug must be enhanced. This is particularly true in fungal diseases where a common symptom of the disease is thickened nail plate. In an onychomycosis study, patients' small toe nails were 5 mm and their large toe nails were 9 mm. When compared to non-infected nail dimensions of 0.5 mm for small toe nails and 1.5 mm for big toe nails, the infected nail presents a formidable barrier to topical treatment.
Nail plates have a high sulphur content in the form of disulfide bonds. U.S. Pat. No. 5,696,164 (Sun et al., 1997) discloses the use of thio-containing amino acids and its derivatives (i.e., sulfhydryl-containing amino acids), such as cysteine and N-acetyl cysteine, and urea to increase drug permeability in a nail plate, by breaking disulfide bonds in nail keratin to increase drug penetration into and through the nail. It was shown that a significant enhancement in topical drug delivery through nail was achieved. European Patent Application EP 503988 A1 (1992) discloses a composition to treat onychomycosis, comprising nail-penetration agents, such as glycols, glycol ethers, dimethyl sulfoxide, caprolactam, and other hydrophilic compounds to facilitate the penetration of allylamine fungicides into the nail.
Nail lacquer, also known as nail coating, polish, enamel and/or varnish, is a popular form of nail care products. A drug-containing nail lacquer is the most convenient and most acceptable nail treatment method to treat nail diseases such as onychomycosis and psoriasis-affected nail. As described above, it is essential to have a drug-containing nail lacquer that is capable of delivering a drug or drugs into and through the nail in therapeutically sufficient quantity. In addition, the drug-containing lacquer should not be irritating to the skin tissue adjacent to the nail. The drug in the lacquer formulations should be stable enough to meet the normally required 2-year shelf life for a pharmaceutical product.
Nail lacquers containing therapeutic agents have been known in the past. For example, U.S. Pat. No. 4,957,730 (1990) describes a nail varnish containing a water-insoluble film-forming substance and antimycotic compound. U.S. Pat. No. 5,120,530 (1992) describes a antimycotic nail varnish containing amorolfine in quaternary ammonium acrylic copolymer. The water-insoluble film former is a copolymerizate of acrylic acid esters and methacrylic acid esters having a low content of quaternary ammonium groups. U.S. Pat. No. 5,264,206 (1993) describes a nail lacquer with antimycotic activity, which contains an antimycotic agent and water-insoluble film formers including polyvinyl acetate, a copolymer of polyvinyl acetate and acrylic acid, copolymers of vinyl acetate and crotonic acid, monoalkyl maleate, etc. U.S. Pat. No. 5,346,692 (1994) describes a nail lacquer for treating onychomycosis, comprised of a film-forming agent, an antimycotically active substance, and urea, wherewith the antimycotic agent and urea are liberated from the lacquer when the lacquer is applied. A preferred formulation comprises cellulose derivatives as film former, clotrimazole as the antimycotic agent, dibutyl phthalate as a plasticizer, and a mixture of acetone and ethanol as solvent. U.S. Pat. No. 5,487,776 (1996) describes a nail lacquer composition which forms a water permeable film containing griseofulvin when the organic solvent system evaporates, wherein a portion of the griseofulvin is in solution and a portion of griseofulvin is present as a colloidal suspension. European Patent Application EP515312 A2 (1992) describes a nail lacquer containing terbinafine or its hydrochloric acid salt as an antimycotic agent, solvents, and a polymeric film former consisting of di-butyl phthalate, Paraloid A-21 acrylic resin, poly(vinyl acetate) etc. However, these patents and publication mention little, if any, information concerning nail penetration enhancement of drugs in these disclosures.
Notwithstanding these instances, however, simply placing a drug in a conventional lacquer formulation without any means of enhancing nail penetration through the nail is unlikely to achieve the desired therapeutic goal. This is particularly true with certain classes of antifungal medication, particularly, azoles and imidazoles. These drugs are often quite insoluble and therefore it is difficult to prepare topical formulations of these drugs. Furthermore, many topical imidazole formulations have been known to be extremely irritating.
Furthermore, when treating onychomycosis, once the nail fungi are killed, the replacement non-infected nails grow relatively slowly. Thus, it can take from six months for non-infected finger nails, and 12 to 18 months for non-infected toe nails to grow and replace discolored and/or deformed. Preferably, a topical product for nail disease treatment, such as onychomycosis, is not only efficacious in eliminating the fungi, but in shortening the waiting period for the healthy nail to grow. U.S. Pat. No. 4,927,626 (1990) describes the topical application of minoxidil to increase the growth of unguis in animals, including human nail. However, it neither describes nor suggests how to deliver the minoxidil through the nail.
The recurrence rate of onychomycosis is relatively high for the patients who have been treated and considered "cured". Because certain people are more prone to onychomycosis, prophylactic products, such as a drug-containing lacquer, are desirable to prevent the relapse of onychomycosis.
Aside from the antifungal diseases associated with nails, there are antifungal diseases associated with human skin. One particular sight of infection is the feet where diseases associated with ring worm, commonly known as athlete's foot, are prevalent.
There are a number of commercial treatments for this disease containing miconazole nitrate as the active ingredient. However, despite these commercial products, a formulation which is capable of delivering a greater percentage of the active ingredient than the commercial products would be useful.
Therefore it is an object of the current invention to prepare a drug-containing composition which is capable of delivering a drug or drugs into and through human nails and skin in a therapeutically sufficient quantity. In addition it is an object of this invention to prepare a composition which adheres to the nail and skin for a prolonged period of time. Further it is an object of the invention to prepare a composition which is non-irritating to human skin. It is still further an object of the invention to prepare a lacquer containing said composition. Further, the composition containing lacquer should not be irritating to the skin tissue adjacent to the nail. Further still, the composition and lacquer should have the shelf required of a pharmaceutical product.